Fifty individuals from 9 families manifesting the von Hippel-Lindau syndrome were evaluated by physical examination including indirect ophthalmoscopy and review of medical records and autopsy records. Analysis of this data combined with a review of 153 documented cases from the literature show that almost all of the morbidity and mortality of the syndrome results from hemangioblastoma of the eye; posterior fossa and spinal cord; pheochromocytoma and renal cell carcinoma. Since successful treatment is available for these lesions, early detection becomes of utmost importance and indirect ophthalmoscopy appears to be the easiest and most effective method of screening at risk family members. In addition serum norepinephrine determination may be valuable in detecting pre-clinical pheochromocytoma as evidenced in one case.